This application is a third submission for a Mentored Patient-oriented Career Development Award (K23) is to support the candidate's development into an independent investigator capable of integrating a solid background and training in neurocognition with the tools of molecular genetics for use in family-based studies of bipolar disorder (BPD). Persistent neurocognitive deficits in BPD during periods of euthymia have aroused interest in neurocognitive dysfunction as an intermediate phenotype, or endophenotype, for studies of its disease susceptibility loci; however, a critical gap in our knowledge exists regarding its familiality or heritability. The endophenotypic criterion of aggregation within families has not yet been convincingly demonstrated among unaffected first-degree relatives of BPD patients. The candidate proposes to first gain the knowledge and training required to collect and analyze data to provide critical validation and refinement of neurocognition as an endophenotype for BPD and to subsequently conduct preliminary research toward this goal. The development plan has three major goals: 1) To expand and refine the candidate's knowledge of the neurocognition of BPD with regard to its use in molecular genetic studies 2) To gain experience in family study methodology including a significant emphasis on understanding molecular genetic models and statistical approaches to integrate quantitative clinical data and molecular genetic data, and 3) To acquire direct research experience and preliminary data on the genetic underpinnings of neurocognitive dysfunction in BPD. To accomplish these aims, a comprehensive didactic program has been prepared. In addition, the candidate will conduct a family-based study of neurocognition in patients with BPD and their unaffected siblings. The research plan proposes to collect comprehensive neurocognitive data in 100 unaffected siblings of BPD patients, 100 stable BPD patients, and 100 demographically-matched healthy volunteers. The feasibility of large-scale implementation of such a viable assay would represent a vital step toward elucidating the genetic underpinnings of BPD. The career development activities and completion of the research study described in this application are expected to provide the candidate with the knowledge and experience to develop into an independent investigator with the expertise to conduct high quality family- based studies that incorporate neurocognition into molecular genetic studies of bipolar disorder. ? ? ?
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